This invention relates to a novel class of partial or full muscarinic receptor agonists, intermediates for their preparation, and pharmaceutical compositions and methods of use for the treatment or prevention of diseases the treatment or prevention of which is mediated by muscarinic receptor agonism. Some compounds described exhibit muscarinic antagonist activity or mixed agonist/antagonist activity and thereby are useful for treatment or prevention of diseases or syndromes characterized by excessive cholinergic activity.
Muscarinic receptors are pre- and post-synaptic receptors in the cholinergic neurotransmitter system. Disruption of the cholinergic neurotransmitter system has been implicated in age related central nervous system (CNS) dysfunction. Muscarinic receptor agonists are believed, by those of ordinary skill in the art, to be useful in treating or preventing age related CNS dysfunction, such as cognitive decline and Alzheimer's disease that results from disruption of the cholinergic neurotransmitter system.
Specific evidence for the role of the cholinergic neurotransmitter system in age related CNS dysfunction has been reported by Bartus, R. T. et al., in The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science, 217, 408-417 (1982). The authors hypothesize that a disruption of the central cholinergic system may be responsible for age-related CNS impairment. (See also, Perry, E. K., The Cholinergic Hypothesis—Ten Years On, Br. Med. Bull., 42, 63-69 (1986)).
Further evidence for the support of the cholinergic hypothesis has been offered by Sims, et al; Presynaptic Cholinergic Dysfunction in Patients with Dementia, J. Neurochem., 40, 503-509 (1983). These authors have demonstrated that the acetylcholine neurotransmitter system is implicated in age-related CNS disorders by showing that activity of cholinergic markers such as choline acetyltransferase is markedly reduced in the brains of patients with Alzheimer's disease (AD) in comparison to age-matched controls.
Additionally, it has been shown that cholinergic neurons which originate at the nucleus basalis of Meynert and project into the hippocampus and cortex show extensive degeneration in Alzheimer's Disease. See Vogel et al. Cell Loss and Shrinkage in the Nucleus Basalis Meynert Complex in Alzheimer's Disease. Neurobiol. Aging, 11, 3-13 (1990); and Whitehouse et al., Alzheimer's Disease and Senile Dermentia: Loss of Neurons in the Basal Forebrain, Science, 215, 1237-1239 (1982).
Furthermore, it has been shown that muscarinic antagonists such as scopolamine can induce cognitive impairments in normal subjects similar to that of normal aging. See Sitaram, et al., Human Serial Learning: Enhancement with Arecoline and Choline and Impairment with Scopolamine. Science, 201, 274-276 (1978); and Drachman D. A. Memory and Cognitive Function in Man: Does the Cholinergic System have a Specific Role? Neurology, 27, 783-790 (1977).
Based on the above research, it is commonly believed that potentiation of central cholinergic action will be a useful treatment of conditions exhibiting cognitive decline.
One strategy to enhance cholinergic neurotransmission has been to mimic the action of acetylcholine at the muscarinic receptors with appropriate agonists. There are three pharmacologically defined receptors (M1-M3) and recently five human receptors (m1-m5) have been cloned (Bonner, et al., Identification of a Family of Muscarinic Acetylcholine Receptor Genes, Science, 237, 527-532 (1987); and Bonner, T. I., The Molecular Basis of Muscarinic Receptor Diversity, T.I.N.S., 12, 148-151 (1989). Due to the lack of highly selective ligands for each subtype, it has not been possible to unambiguously establish the biological role of the individual receptors. However, it is believed that central m1 receptors mediate cognition and the m2-m5 subtypes are responsible for side effects (salivation, lacrimation, diarrhea). Immunoprecipitation studies have shown a preponderance of the human m1 receptor in the cortex and hippocampus, areas of the brain involved in memory and learning. Ideally, a selective m1 agonist would be a desirable agent for treating the cognitive decline associated with neurodegenerative disorders.
In addition to age related cognitive decline, muscarinic agents are also known to be effective in the treatment of psychotic conditions, pain, sleep disorders, depression, seasonal affective disorder and tardive dyskinesias.
Muscarinic agents are known to influence schizophrenia and other psychotic conditions and the atypical antipsychotic clozapine possesses selective m4 agonist activity which is important for its clinical profile (Zorn et al., Clozapine Is A Potent And Selective Muscarinic M4 Receptor Agonist, Eu. J. Pharmacol., 269, R1-R2, (1994). Clozapine is also used to treat the tardive dyskinesias that frequently arise following treatment with typical antipsychotics.
Muscarinic agonists are also known to produce robust analgesia, comparable to that produced by opiate analgesics. (P. Hartvig et al., Cholinergic mechanisms in pain and analgesia, Trends Pharmacol. Sci., 9, 75-79, (1989)).
Muscarinic antagonists are also believed to be effective agents in treating diseases or syndromes characterized by overactivation of muscarinic receptors. Cholinergic regulation of sleep, particularly the REM phase, indicates that the muscarinic agents will be useful in treating sleep disorders such as insomnia and somnolence (D. Reimann et al., Cholinergic Neurotransmission, REM Sleep And Depression, J. Psychosom. Res., 38, 15-25, (1994)). Muscarinic systems also modulate psychiatric depression (K. Davis et al., Induction of Depression With Oxotremorine In Patients With Alzheimer's Disease, Am. J. Psychiatry, 144, 468-471, (1987)), including seasonal affective disorder (S. C. Dilsaver et al., Bright Artificial Light Subsensitizes a Central Muscarinic Mechanism, Life Sci., 41, 2607-2614, (1987)).
Muscarinic antagonists are also useful in the treatment of diseases associated with altered motility or tone of smooth muscle such as irritable bowel syndrome, urinary incontinence, diverticular disease, oesophageal achalasia and chronic obstructive airways disease.
U.S. Pat. No. 4,211,867, issued Jul. 8, 1980, refers to nitrogen heterocyclic carboximidamide derivatives. The compounds are stated to possess hypoglycemic activity.
U.S. Pat. No. 4,414,211, issued Nov. 8, 1983, refers to heterocyclic derivatives of guanidine. The compounds are stated to possess hypoglycemic activity.